1. Field of the Invention
The present invention generally relates to a neurodegenerative non-human transgenic animal. In particular, the present invention relates to a neurodegenerative non-human transgenic mammal expressing the TrkA recombinant protein and the use thereof.
2. Description of Related Art
As the median of the industrialized world's population increases gradually, age-related diseases are becoming a major public health challenge. Most significantly, neurodegenerative diseases affect a large sector of the elderly population. Alzheimer's disease (AD) is the most common neurodegenerative disorder and the most common cause of dementia. AD is typified by progressive memory loss, impairment in judgment, decision making, orientation and language. On the cellular level, AD is characterized by the deposition of amyloid plaques outside nerve cells, the accumulation of abnormal protein filaments inside nerve cells in the brain and neuronal loss. Epidemiology studies indicate that Alzheimer's diseases alone affect about one tenth of the population over 65 years of age. For example, in the United States, more than four millions people suffer from the disease, and the economic impact of the disease exceeds billions of dollars. It is estimated that by the year of 2025, more than 22 millions of the world population will be inflicted with some forms of Alzheimer's disease. Therefore, the developments of effective prevention methods and cures are imminently required.
Currently, means for an early diagnosis and an appropriate treatment of the various neurodegenerative diseases such as AD are lacking. A development of a drug or animal model is essential for studying the mechanisms underlying AD and testing the efficacy of new drugs. The unavailability of a suitable animal model hampers the screening of new therapeutic agents. The current animal models are transgenic animals produced with mutated genes from familial Alzheimer's, which can only represent 5% of the AD patients. Absence of a comprehensive model for AD, the development of new drugs and defining the etiopathogenesis of the disease will be limited.
Nerve growth factor (NGF) (Levi-Montaicini, 1952, “Effects of mouse tumor transplantation on the nervous system” Ann N Y Acad Sci. 55(2):330-44) is a member of a family of peptides known as neurotrophins which are essential in the developments and survival of certain sympathetic and sensory neurons in both the central and peripheral nervous systems. Other members of the neurotrophin family include brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). There are two classes of receptors, p75 and the Tyrosine kinases. The receptor p75 is a low affinity neurotrophin receptor, to which all neurotrophins bind. The Tyrosine kinases include TrkA, TrkB, and TrkC, and will only bind with specific neurotrophins at a higher affinity. NGF binds to two classes of cells surface receptors: the p75 receptor and the TrkA receptor. The binding of NGF to TrkA initiates the neuronal signaling pathway. BDNF and NT-4 bind to TrkB receptors while NT-3 specifically interacts with TrkC receptors. However, NT-3 can also activate TrkA and TrkB receptors under certain conditions. Similarly, NT-4 also binds to TrkA with lower affinity.
Trangenic animals lacking sufficient nerve growth factor (NGF) suffer from neruoronal damage and behavioral disorder. Depletion of extracellular NGF by the administration of neutralizing antibodies (anti-NGF) has been shown to result in a neurodegenerative phenotype resembling AD in aged transgenic animal model. However, such a model can only focus on the signaling pathway of NGF. On the other hand, a Trk receptor deficient animal model may provide a more comprehensive understanding on the tropic actions of the various neurotrophins.